The myelodysplastic syndromes (MDS) are characterized by cytopenias in one or more hematopoietic lineages as a result of ineffective and dysplastic hematopoiesis. Myelodysplastic syndromes are increasing in incidence as the population ages, and patients with these disorders experience complications from cytopenias and may have progression to acute leukemia. In MDS, the mechanisms underlying stem cell abnormalities are not well understood. Increased apoptosis has been noted as well as abnormalities in cytokines such as TNF-a and other cellular, angiogenic, and cytokine elements of the marrow microenvironment. The agent, bortezomib, a proteasome inhibitor, may have anti-proliferative effects on malignant vs. normal cells, may inhibit NF-kB, often activated in MDS marrows, and may alter tumor cell/microenvironment interactions. Given the parallels of bortezomib's actions with the abnormalities found in MDS, we will examine its use in MDS in a single-arm phase II clinical trial and will conduct correlative in vitro studies to test the hypothesis that bortezomib will inhibit progenitor cells in MDS by inducing a pro-apoptotic state. To test this hypothesis, the following aims are proposed: 1) To determine the effect of bortezomib as a single agent in the therapy of myelodysplastic syndromes through conduct of a clinical trial; 2) To determine the effects of bortezomib both in vivo and in vitro on hematopoiesis and the hematopoietic stem cell in myelodysplasia. Effects on apoptosis, clonogenic progenitors, and stoma cell cytokine milieu will be determined, and 3) To assess the effects of bortezomib on inhibition of NF-kB and on pathways associated with cell death and/or survival in hematopoietic cells such as the Erk and Akt pathways. These studies will define a potential therapeutic role for bortezomib in MDS and will aid in understanding the hematopoietic stem cell in these disorders.